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Lucas Cheadle

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By Daniel Dunaief

A male mouse embryo surrounded by a group of female embryos during development in some cases is protected against developmental delays caused by a viral infection of their mother.

That’s one of a host of intriguing observations and findings from a recent set of experiments conducted by postdoctoral researcher Irene Sanchez Martin, who works in the lab of Assistant Professor Lucas Cheadle at Cold Spring Harbor Laboratory.

Irene Sanchez Martin and Lucas Cheadle at Cold Spring Harbor Laboratory. Photo by Justin Park

Sanchez Martin is studying how maternal exposure to viruses triggers immune responses, particularly inflammation, which can contribute to developmental delays characteristic of autism. 

In mice as in humans, males are much more susceptible to the onset of the kinds of neurological developmental behaviors that are characteristic of autism than their female counterparts.

“The advantage of our model is that it helps us understand why this happens, providing insights into the underlying mechanisms driving this increased vulnerability in males,” Sanchez Martin explained.

Researchers have been studying viral exposure and developmental disorders for a while. The new element in Sanchez Martin’s research is that she can observe phenotypic changes as early as 24 hours after a pregnant mouse is exposed to a virus, providing a much earlier window into how maternal immune activation affects development.

At an early stage of gestation, when sensory organs, the head, spine and other organs are starting to develop, the male mice demonstrate disruptions in normal development, which affects these structures in different ways. Sanchez Martin hopes these kinds of studies help uncover the pathways through which environmental factors contribute to the development of some cases of autism.

Sanchez Martin’s work is part of a broader effort in Cheadle’s research.

“My lab is interested in understanding how interactions between the nervous system and the immune system shape the development and plasticity of the brain,” Cheadle explained. One goal is to understand how systemic inflammation during prenatal stages leads to heightened risk of autism in offspring.

To be sure, the genetic component suggests that inflammation is not necessary for the development of autism. Nevertheless, exposure to prenatal inflammation can increase autism risk by about three times, making inflammation a likely “key contributor to the development of autism in some, but not all, individuals,” said Cheadle.

Sanchez Martin found that female mice did not develop the same changes as males. She believes this is one of the most valuable applications of the model she’s working on with Cheadle, as it can reveal the biological and developmental differences that contribute to this gender disparity.

Timing

Sanchez Martin studied mice that were exposed to a virus between 12 to 13 days after fertilization, which is similar to the end of the first trimester in a human embryo. Mice develop more rapidly, so the process doesn’t track exactly the same as it would in humans.

About a day after the maternal exposure, some males looked different through ultrasound than they would during typical development. The differences are subtle and it is still too early to assume these changes could serve as a diagnostic marker for autism spectrum disorder.

A host of disruptions could affect the growth of the embryo. The placenta serves as a bridge between the mother and the developing embryo, allowing communication, filtering substances, and protecting the embryo during development. Each mouse embryo has its own placenta and its own amniotic fluid in its amniotic sac, creating a unique microenvironment.

In her lab work, Sanchez Martin is collaborating with Dr. Brian Kalish at Boston Children’s Hospital, who is helping to analyze molecular changes in the placentas of affected and unaffected embryos. Sanchez Martin has data indicating differences between the placentas of affected and healthy individuals, as well as in the amniotic fluid.

“This suggests a dysfunction in the placenta in affected cases” indicating it is not adequately performing its protective and filtering function, she explained.

Female mouse embryos may be more protected in part because of their more active immune response. Other studies have shown that female immune systems, as early as the developmental stage, express higher levels of interferon-stimulated genes and have stronger responses to infections, which may offer better protection than males.

While male mice in some cases benefit from the protection provided by their nearby sisters, Sanchez Martin and Cheadle are “still working to fully understand the underlying mechanism,” she explained.

Epidemiology

By looking at the prevalence of conditions such as autism in the aftermath of larger viral infections, researchers have demonstrated that these illnesses can and do have impacts on the incidence of autism and schizophrenia, among other conditions. It’s not only the pathogen that is responsible, but also the immune response triggered by the infection, as well as the timing of the infection during pregnancy.

Covid, which infected over 100 million Americans, may cause an increase in the number of children born with autism.

“There is precedent from studies of other viral infections during pregnancy, which suggest that maternal immune activation can contribute to altered neurodevelopment in offspring,” Sanchez Martin said. “There is some evidence that male children exposed to SARS-CoV-2 during pregnancy might have a slightly elevated risk of other neurodevelopmental disorders.”

Additional research with longer-term follow up is necessary to confirm these findings. The timing and the immune response during pregnancy could be key factors in determining the outcomes​​.

Cheadle appreciated the effort and dedication of Sanchez Martin, whom he described as being “bright, talented, motivated and an excellent experimentalist. Her work is among the most important projects in the lab.”

From Madrid to CSHL

Born and raised in Madrid, Spain, Sanchez Martin has been a master of motion. During her final years of her Veterinary Medicine studies at Universidad Alfonso X El Sabio in Madrid, she moved to the University of Helsinki to complete her clinical rotations.

She later earned her PhD at the Centre National de la Recherche Scientifique in Marseille, France and defended her thesis at the Aix- Marseille University. During her PhD, she was a visiting student at Biocenter Oulu in Finland.

Her first job was at Laboklin in Bad Kissingen, Germany, where she worked in a clinical laboratory.

She did her first postdoctoral research in the Microbiology Department at Mount Sinai. During the pandemic, she was involved in studying innate and adaptive immune responses in different in vitro models, focusing on vaccine candidates for Covid-19 and influenza.

A resident of Manhattan, Sanchez Martin has contributed to Cheadle’s lab for two years.

She enjoys listening to classical music, reading, and swimming, which she likes to do several times a week as she has some of her best ideas when she’s in the water.

As for her work, Sanchez Martin appreciates the opportunity to conduct her research as a part of Cheadle’s team that is hoping to identify the molecular mechanisms that contribute to autism in mice.

“It’s an ongoing effort and we hope that with time and collaboration, we can gain more insight,” she explained.

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Lucas Cheadle with two pieces of artwork in his office, from left by Porferio Tirador 'Gopher' Armstrong, a Cheyenne-Caddo native from Oklahoma and Oklahoma Kiowa artist Robert Redbird. Photo by Austin Ferro

By Daniel Dunaief

Cold Spring Harbor Laboratory Assistant Professor Lucas Cheadle knows a thing or two about under represented groups in the field of Science, Technology, Engineering and Mathematics.

Of Chickasaw, Choctaw and Cherokee lineage, Cheadle, who was born in Ada, Oklahoma, was recently named one of 31 inaugural Howard Hughes Medical Institute’s (HHMI) Freeman Hrabowski scholars.

Lucas Cheadle. Photo by Steve Ryan/ AP Images for HHMI

The first scholars in this highly competitive and unique program, which drew 1,036 applicants, will receive funding that will last at least five years and could get as much as $8.6 million each for their promising early research and for supporting diversity, equity and inclusion in their labs.

“This is the first time a program of this type and magnitude has been attempted,” said HHMI Vice President and Chief Scientific Officer Leslie Vosshall. The scholars are “doing things that set them in the top one percent in creativity and boldness and we are certain we are going to have really healthy, inclusive, diverse labs.”

Vosshall said the scholars, which include scientists from 22 institutions, including Columbia, Harvard, Duke, Cornell, Princeton, the University of Pennsylvania, and Massachusetts Institute of Technology, hit it “out of the park” in their science and diversity efforts.

HHMI, which has committed $1.5 billion for Freeman Hrabowski Scholars, will award about 30 of these select scholarships every other year for the next 10 years, supporting promising scientists who can serve as mentors for under represented groups while also creating a network of researchers who can provide advice and collaborations.

The first group of scientists to receive this support is “diverse in such a way that it reflects the U.S. population,” Vosshall said.

The program is named after Freeman Hrabowski, who was born in Birmingham, Alabama and was president of the University of Maryland, Baltimore County, from 1992 to 2022. Hrabowski, who was arrested during the civil rights movement, created a tutoring center in math and science for African Americans in high school and college and helped create the Meyerhoff Scholars Program.

Cheadle was celebrating the December holidays in Oklahoma when he learned he was a semifinalist, which was “really surprising and exciting,” he recalled. Becoming an HHMI scholar is “amazing” and “very validating,” he said.

Bruce Stillman, President and CEO of CSHL, suggested that HHMI recognition is “a prestigious achievement” and, in a email, wrote that he was “pleased that [Cheadle] was included in the list of remarkable scientists.”

Stillman predicted that Cheadle’s passion about increasing diversity in science would have a “major influence” on CSHL.”

Scientific questions

Cheadle appreciates how HHMI funds the scientist, not individual projects. With this unrestricted funding, which includes full salary and benefits and a research budget of about $2 million over the first five years and eligibility to participate in HHMI capital equipment purchasing programs, Cheadle and other scholars can pursue higher-risk, higher-reward projects.

“If I have a crazy idea tomorrow, I can do that with this with funding,” Cheadle explained.

Cheadle, who joined CSHL in August of 2020, studies the way the immune system shapes brain development, plasticity and function. He also seeks to understand how inflammatory signals that disrupt neural circuit maturation affect various disorders, such as autism.

Last September, Cheadle and his lab, which currently includes six postdoctoral researchers, two PhD students, one master’s student, a lab manager and two technicians, published a paper in Nature Neuroscience that showed how oligodendrocyte precursor cells, or OPCs, help shape the brain during early development.

Previously, scientists believed OPCs produced cells that surrounded and supported neurons. Cheadle’s recent work shows that they can play other roles in the brain as well, which are also likely instrumental in neural circuit construction and function.

When young mice raised in the dark received their first exposure to light, these OPCs engulfed visual processing circuits in the brain, which suggested that they helped regulated connections associated with experience.

With this new position and funding, Cheadle also plans to explore the interaction between the development of nerves in the periphery of the brain and different organs in the body, as well as how immune cells sculpt nerve connectivity.

He is not only studying this development for normal, healthy mice, but is also exploring how these interactions could explain why inflammation has arisen as such an important player in neurodevelopmental dysfunction.

Stillman explained that Cheadle’s work will “have broad implications.”

A talented, balanced team

Cheadle is committed to creating a balanced team of researchers from a variety of backgrounds.

“As principal investigators,” Cheadle said, “we have to actively work to have a diverse lab.”

He has posted advertisements on women’s college forums to garner more applications from women and under represented groups. He has also adopted a mentorship philosophy that focuses on inclusivity. 

Cheadle explained that he hopes to be adaptable to the way other people work. Through weekly lab meetings, mentorship arrangements and reciprocal interactions, he hopes to provide common ground for each aspiring scientist.

He recognizes that such goals take extra effort, but he feels the benefits outweigh the costs.

During annual events, Cheadle also leans in to the cultural diversity and differences of his staff. He hosts a pre-Thanksgiving pot luck dinner, where everybody brings a food item that’s important and close to them. 

Last year, he made pashofa out of cracked corn that his stepmom sent him from the Chickasaw Nation in Oklahoma. Pashofa is a traditional meat and corn Chickasaw dish. Other lab members brought tropical beverages common in Brazil.

In terms of diversity in science, Cheadle believes such efforts take years to establish. Through an approach that encourages people from different backgrounds to succeed in his lab, Cheadle hopes to share his thoughts and experiences with other researchers.

Cheadle last summer hosted a Chickasaw student on campus to do research. He is working with the Chickasaw Nation to expand that relationship.

As for the Freeman Hrabowski scholars, Vosshall said all HHMI wants to do is “allow everybody to do science.-

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HHMI Chief Scientific Officer Vosshall celebrates benefits of diversity in science

By Daniel Dunaief

It’s not one or the other. She believes in both at the same time. For Leslie Vosshall, Vice President and Chief Scientific Officer at Howard Hughes Medical Institute, science and diversity are stronger when research goals and equity work together.

Leslie Vosshall. Photo by Frank Veronsky

That’s the mission of the new and unique HHMI Freeman Hrabowski Scholars program. HHMI this week named 31 inaugural scholars as a part of an effort designed to support promising scientists who provide opportunities to mentor historically under represented groups in research.

Cold Spring Harbor Laboratory Assistant Professor Lucas Cheadle was among the 31 scientists who became HHMI scholars (see related story above), enabling him to receive financial support for the next five years and up to $8.6 million for the next decade.

In an interview, Vosshall said the “special sauce of this group” of scientists who distinguished themselves from among the 1,036 who applied was that they excel as researchers and as supporters of diversity. Bringing in people who may not have had opportunities as scientific researchers not only helps their careers but also enables researchers to take creative approaches to research questions.

“When you bring in people from the ‘out group’ who have been historically excluded, they have an energy of getting into the playing field,” she said. That innovation can translate into successful risk taking.

As an example, Vosshall cited Carolyn Bertozzi, a chemist at Stanford University who shared the 2022 Nobel Prize in Chemistry for helping to develop the field of bioorthogonal chemistry, which involves a set of reactions in which scientists study molecules and their interactions in living things without interfering with natural processes.

Her lab developed the methods in the late 1990’s to answer questions about the role of sugars in biology, to solve practical problems and to develop better tests for infectious diseases. “This scrappy band of women chemists tried this crazy stuff” which provided “massive innovations in chemical biology,” Vosshall said. Mainstream science often solidifies into a groove in which the same thing happens repeatedly. “Innovation comes from the edges,” she added.

In her own to hire staff in her lab, Vosshall has taken an active approach to find candidates from under served communities. “People who have pulled themselves up have worked so hard to get to where they are,” she said. “It’s important to dig deeper to find talent everywhere.”

Keeping away from the off-ramp

The number of under represented groups in science has improved over the last few decades. Indeed, when Vosshall joined Rockefeller University, where she is the Robin Chemers Neustein Professor, she couldn’t count 10 women faculty. Now, 23 years later, that number has doubled.

The number of people in under represented groups in graduate programs has increased. The problem, Vosshall said, is that they “take the off-ramp” from academic science” because they don’t always feel “welcome in the labs.” Supporting diversity will keep people in academic science, who can and will make important discoveries in basic and translational science.

As a part of the Freeman Hrabowski program, HHMI plans to survey people who were trainees in these labs to ask about their mentoring experience. By tracking how developing scientists are doing, HHMI hopes to create a blueprint for building diversity.

HHMI has hired a consultant who will analyze the data, comparing the results for the results and career trajectories. The research institute will publish a paper on the outcome of the first cohort. Researchers in this first group will not only receive money, but will also have an opportunity to interact with each other to share ideas.

New approach

When Vosshall earned her PhD, she considered an alternative career. She bought a training book for the Legal Scholastic Aptitude Test and considered applying to law school, as she was “fed up with how I was treated and fed up with science”

Nonetheless, Vosshall, who built a successful scientific career in which she conducts research into olfactory cues disease-bearing insects like mosquitoes seek when searching for humans, remained in the field.

To be sure, Vosshall and HHMI aren’t advocating for principal investigators to hire only people from under represented groups. The promising part of this scholarship is that HHMI found it difficult to get the final number down to 31, which “makes me optimistic that the [scientific and mentorship] talent is out there,” she said. Over the next decade, HHMI plans to name about 30 Freeman Hrabowski scholars every other year. If each lab provides research opportunities across different levels, this will help create a more diverse workforce in science, which, she said, benefits both prospective researchers and science.

 

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Taken around 1890, the photo above includes Lucas Cheadle’s great, great grandparents Martin Van Buren Cheadle and his wife Mary Vera with their children, from left, Overton, Ellis, Lurena and Thomas (who is Cheadle’s great grandfather).

By Daniel Dunaief

In joining Cold Spring Harbor Laboratory, Lucas Cheadle has continued his professional and personal journey far from his birthplace in Ada, Oklahoma.

Then again, his travels, which included graduate work in New Haven at Yale University and, most recently, post doctoral research in Boston at Harvard Medical School, wasn’t nearly as arduous or life threatening as the forced trip his ancestors had to take.

In 1837, Cheadle’s great, great, great grandparents had to travel from Pontotoc, Mississippi to southern Indian Territory, which is now near Tishomingo, Oklahoma as a part of the Trail of Tears. Native American tribes, including members of Cheadle’s family who are Chickasaw, cleared out of their lands to make way for Caucasian settlers.

Lucas Cheadle

Proud of his biracial heritage, which includes Chickasaw, Choctaw, and Cherokee lineages, Cheadle hopes to make his mark professionally in his studies of the development of the brain (see article on page B). At the same time, he hopes to explore ways to encourage other members of the Chickasaw tribe to enter the fields of science, technology, engineering and mathematics.

One of three sons of a mixed Chickasaw father named Robert Cheadle and a Caucasian mother named Cheryl, Cheadle would eventually like to provide the kind of internship opportunities through his own lab that he had during his high school years.

Indeed, during the summer of his junior year, Cheadle did a health care internship, in which he shadowed different types of physicians. He watched active surgeries and observed a psychiatrist during patient visits. After that summer, Cheadle thought he might become a psychiatrist as well because he knew he was interested in the study of the brain.

Down the road, Cheadle envisions having one or two people learn as interns in the lab during the summer. Longer term, Cheadle hopes other investigators might also pitch in to provide additional scientific opportunities for more Native American high school students.

Growing up in Oklahoma, Cheadle never felt he stood out as a member of the Chickasaw tribe or as a biracial student.

His father, Robert, was active with the tribe, serving as a tribal judge and then as a legislative attorney for the Chickasaw. His grandfather, Overton Martin Cheadle, was a legislator.

Through their commitment to the Chickasaw, Cheadle felt a similar responsibility to give back to the tribe. “It was an incredibly important part of their professional lives and it was a passion” to help others, he said. “I’m driven by that spirit.”

His father took people in who had nowhere to go. In a few cases, people he put up robbed the family. Even after they robbed him, Cheadle’s father took them back. When Robert Cheadle died earlier this year, one of the people whom Cheadle supported helped out with his funeral arrangements.

Driven to accomplish his mission as a scientist, Lucas Cheadle feels he can reach out to help high school students and others interested in science during his research journey.

“The better I can do, the more I can help,” Cheadle said. He hopes to “open doors for other people.”

With some of these efforts to encourage STEM participation among Native Americans, Cheadle hopes to collaborate with John Herrington, a Chickasaw astronaut who took a Native American flute into space during one of his missions. “It would be wonderful to discuss this” with Herrington, “if he has time for me,” said Cheadle.

In modern times, the Chickasaw tribe has made “good strides” in being successful. One challenge to that success, however, is that it has included assimilation.“The main goal is to hold onto the heritage as much as we can,” said Cheadle.

As for now, he plans to honor his heritage in his lab by “working hard to create a safe, respectful environment where people’s unique backgrounds and characteristics are supported and embraced. I try to create a space where diversity can thrive.”

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Lucas Cheadle. Photo from CSHL

By Daniel Dunaief

One of the newest additions to Cold Spring Harbor Laboratory’s neuroscience program, Lucas Cheadle, who is an assistant professor, is exploring the early environmental factors at a molecular level that shape the neurological development of the mouse visual system.

While nature and nurture combine to produce the individuals each life form becomes, Cheadle is focused on the ways nurture, specifically, shapes the pathways in the brain that affect the development of sight.

Microglia are an unlikely player in this environmentally-triggered development, as doctors and researchers previously saw these cells primarily as participants in neurinflammation.

That is not the case anymore, with Cheadle and other scientists demonstrating over the past decade or so that microglia play important parts in the healthy brain. Cheadle, specifically, has demonstrated that these cells play a role in experience-dependent circuit development.

Indeed, the process of circuit refinement in the developing brain, which Cheadle describe as being among the “most complex structures in the known universe,” is akin to a room full of half-full boxes, which represent synaptic connections between neurons.

The brain begins with numerous little boxes that make the room difficult to navigate. As the brain consolidates the important items into a smaller number of larger boxes and removes the smaller boxes, the room becomes more manageable.

This is consistent with what Cheadle has seen during refinement. A smaller number of synapses become stronger and are maintained, while others are removed. This promotes the efficiency and precision of neural processing, he explained.

When the contents of some of those boxes disappear, however, the result can lead to neurodegenerative diseases like Alzheimer’s, in which a person struggles to find memories that may have been unwittingly cleared out.

Cheadle, who most recently was a post doctoral researcher at Harvard Medical School, is exploring the way microglia shape the connections between the eyes and the brain between when a mouse is born and when it reaches one month of age.

His work has shown that microglial cells are required for the sensory-dependent phase of visual circuit development. Disrupting signals between microglia and neurons affects synapse elimination, akin to removing the smaller boxes, which is important for circuit function.

Indeed, prior to work Cheadle and others have done in recent years with these cells in the brain, researchers thought microglia in the brain were quiescent, or inactive, after birth, except for their role in brain injury, disease pathology and neuroinflammation.

Until the first week of life, microglia engulf and then digest synaptic connections between some neurons, in a process called phagocytosis. During the sensory-dependent phase of refinement in the third week after birth, which Cheadle demonstrated in a paper published this month in the journal Neuron, microglia stop phagocytosis and rely on cytokines to break down synapses.

The cytokine pathway Cheadle discovered, called TWEAK, which is a ligand expressed by microglia, and Fn14, a receptor expressed by neurons, becomes active between eye opening, which is around two weeks, and peaks at about four weeks old.

When mice don’t have exposure to important visual stimuli during this critical period, the circuit has too many synaptic connections, which reduces the effectiveness of the developing visual system.

While Cheadle is working on visual development, specifically, he is interested in the broader implications of this work in the context of the environmental signals that affect the development of the brain.

In that broader context, the processes involved in autism and schizophrenia could reflect a period in which individuals have an overabundance of synapses that weren’t sufficiently pruned and refined.

Despite the fact that researchers hypothesized that synaptic pruning may lead to these disorders decades ago, they still have a limited awareness of whether and how this might happen. Studying the way microglia contribute to healthy circuit development could provide important clues about these processes.

Some epidemiological evidence points to the linkage between immune activity and neurodevelopmental disorders. In 1918 and 1919, during the Spanish Flu pandemic, children born during that period had a higher incidence of an autism or schizophrenia later in life.

Other evidence shows an interaction between immune activation and neurodevelopmental dysfunction, including the genetic loci associated with such disorders and increased inflammatory markers in the blood and brains of people with such disorders. “There’s really no question that there is a link,” Cheadle explained. “The nature of the link is still poorly understood.”

While earlier epidemiological data raises questions about the current pandemic, it doesn’t provide a definitive answer because “we still don’t quite understand what the nuanced molecular factors are that link the immune activation to the increase in disease prevalence,” Cheadle suggested.

“There’s a real chance that having COVID during pregnancy may impact the development of the offsprings’ nervous systems as has been seen in other infections,” Cheadle wrote. “While it is not the current priority of COVID research, it certainly warrants studying.”

Cheadle hopes to understand the “underlying principals of disorders” he said.

A resident of Huntington, Cheadle lives five minutes from the lab. He plans to rent for now because he didn’t want to start a new lab and move into a new house at the same time.

Cheadle has hired a technician and is in the process of hiring another. A post doctoral scientist will join his lab in November.

Early on in his life, Cheadle said he was fascinated with the interface between the world and biology. He wanted to understand how human brains interpret the information that comes from our senses. Everything culminated, professionally, in his interest in neurobiological mechanisms.

Currently, Cheadle is also interested in the looming behavior of mice. In the field, when mice see a bird that is flying slowly overhead, they are more likely to make a mad dash for safety, running into weeds or for cover from a tree. When the bird, however, is flying too rapidly, the mice freeze.

“I’m intrigued to find out whether the dichotomy of fight or flight could be shifted by the function of microglia,” he said. “I like to understand something at a functional level and dissect it to a molecular level.”

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